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Immunogenicity and safety of beta variant COVID-19 vaccine AZD2816 and AZD1222 (ChAdOx1 nCoV-19) as primary-series vaccination for previously unvaccinated adults in Brazil, South Africa, Poland, and the UK: a randomised, partly double-blinded, phase 2/3 non-inferiority immunobridging study.

BACKGROUND: AZD2816 is a variant-adapted COVID-19 vaccine that expresses the full-length SARS-CoV-2 beta variant spike protein but is otherwise similar to AZD1222 (ChAdOx1 nCoV-19). This study aimed to evaluate the safety and immunogenicity of AZD1222 or AZD2816 (or both) primary-series vaccination in a cohort of adult participants who were previously unvaccinated. METHODS: In this phase 2/3, randomised, multinational, active-controlled, non-inferiority, immunobridging study, adult participants previously unvaccinated for COVID-19 were enrolled at 16 study sites in Brazil, South Africa, Poland, and the UK. Participants were stratified by age, sex, and comorbidity and randomly assigned 5:5:5:2 to receive a primary series of AZD1222 (AZD1222 group), AZD2816 (AZD2816 [4-week] group), or AZD1222-AZD2816 (AZD1222-AZD2816 group) at 4-week dosing intervals, or AZD2816 at a 12-week interval (AZD2816 [12-week] group) and evaluated for safety and immunogenicity through 180 days after dose 2. Primary outcomes were safety (rates of solicited adverse events occurring during 7 days and unsolicited adverse events occurring during 28 days after each dose) and immunogenicity (non-inferiority of pseudovirus neutralising antibody geometric mean titre [GMT], GMT ratio margin of 0·67, and seroresponse rate, rate difference margin of -10%, recorded 28 days after dose 2 with AZD2816 [4-week interval] against beta vs AZD1222 against ancestral SARS-CoV-2) in participants who were seronegative at baseline. This trial is registered with ClinicalTrials.gov, NCT04973449, and is completed. FINDINGS: Between July 7 and Nov 12, 2021, 1449 participants were assigned to the AZD1222 group (n=413), the AZD2816 (4-week) group (n=415), the AZD1222-AZD2816 group (n=412), and the AZD2816 (12-week) group (n=209). Ten (2·6%) of 378 participants who were seronegative at baseline in the AZD1222 group, nine (2·4%) of 379 in the AZD2816 (4-week) group, eight (2·1%) of 380 in the AZD1222-AZD2816 group, and 11 (5·8%) of 191 in the AZD2816 (12-week) group had vaccine-related unsolicited adverse events. Serious adverse events were recorded in one (0·3%) participant in the AZD1222 group, one (0·3%) in the AZD2816 (4-week) group, two (0·5%) in the AZD1222-AZD2816 group, and none in the AZD2816 (12-week) group. Co-primary immunogenicity endpoints were met: neutralising antibody GMT (ratio 1·19 [95% CI 1·08-1·32]; lower bound greater than 0·67) and seroresponse rate (difference 1·7% [-3·1 to 6·5]; lower bound greater than -10%) at 28 days after dose 2 were non-inferior in the AZD2816 (4-week) group against beta versus in the AZD1222 group against ancestral SARS-CoV-2. Seroresponse rates were highest with AZD2816 against beta (12-week interval 94·3% [95% CI 89·4-97·3]; 4-week interval 85·7% [81·5-89·2]) and with AZD1222 (84·6% [80·3-88·2]) against ancestral SARS-CoV-2. INTERPRETATION: Primary series of AZD1222 and AZD2816 were well tolerated, with no emergent safety concerns. Both vaccines elicited robust immunogenicity against beta and ancestral SARS-CoV-2 with greater responses demonstrated when testing against SARS-CoV-2 strains that matched those targeted by the respective vaccine. These findings demonstrate the continued importance of ancestral COVID-19 vaccines in protecting against severe COVID-19 and highlight the feasibility of using the ChAdOx1 platform to develop COVID-19 vaccines against future SARS-CoV-2 variants. FUNDING: AstraZeneca.

Biomarkers of vaccine safety and efficacy in vulnerable populations: Lessons from the fourth international precision vaccines conference

Vaccination has been a cornerstone of public health, substantially reducing the global burden of infectious diseases, notably evident during the COVID-19 pandemic caused by SARS-CoV-2. However, vulnerable populations (VPs), including those in extreme age groups and those with underlying health conditions, have borne a disproportionate burden of morbidity and mortality from infectious diseases. Understanding vaccine immunogenicity in these populations is crucial for developing effective vaccines. Characterizing vaccine responses in VPs presents unique challenges due to under-vaccination, sub-optimal vaccine responses, and distinct mechanisms of vaccine-induced protection. To address these challenges, experts convened at the 4th International Precision Vaccines Conference in Rome. Co-hosted by the Precision Vaccines Program of Boston Children's Hospital and Ospedale Pediatrico Bambino Gesù, the conference focused on biomarkers of vaccine safety and efficacy in vulnerable populations. Discussions at the conference emphasized the need for multidisciplinary strategies and international collaborations to optimize vaccine development. Key areas of focus included assessing vaccine safety, defining biomarkers for vaccine immunogenicity, developing human in vitro assay models, and accelerating the selection of novel vaccine formulations and adjuvants tailored for vulnerable populations. The conference provided a platform for experts from diverse fields, including immunology, paediatrics, and vaccinology, to exchange ideas and advance research in precision vaccines. This manuscript highlights key concepts discussed at the conference and underscores the importance of precision vaccines in addressing the unique needs of vulnerable populations.

The Epidemiology, Clinical, and Economic Burdens of Respiratory Syncytial Virus Infections Amongst Hospitalized Children Under 5 Years of Age in Jordan: A National Multi-Center Cross-Sectional Study

Respiratory syncytial virus (RSV) has been recognized as a highly important cause of morbidity and mortality among children and adults. A cross-sectional study at representative sites in Jordan was undertaken to provide an assessment of the epidemiology and health and economic burdens of RSV and influenza infections in Jordan amongst hospitalized children under 5 years old for the period between 15 November 2022 and 14 April 2023. This study involved 1000 patients with a mean age of 17.10 (SD: 16.57) months. Of these, half (n = 506, 50.6%) had positive results for RSV. Furthermore, 33% and 17.4% of the participants had positive results for RSV-B and RSV-A, respectively. The findings underscore the severity of RSV infections, where a significant proportion of the children experienced severe respiratory distress, which led to bronchiolitis and pneumonia. This study meticulously documented the clinical outcomes, including the need for intensive care, mechanical ventilation, and prolonged hospital stays. There was no statistically significant difference in the financial burdens between the RSV-positive and RSV-negative patients. This study revealed the urgent need for preventive measures to control the substantial burden of RSV among children under 5 years old in Jordan.

Five-Year Vaccine Protection Following a Single Dose of Vi-Tetanus Toxoid Conjugate Vaccine in Bangladeshi Children: A Cluster Randomised Trial

COVID-19 testing and reporting behaviours in England across different sociodemographic groups: a population-based study using testing data and data from community prevalence surveillance surveys.

BACKGROUND: Understanding underlying mechanisms of heterogeneity in test-seeking and reporting behaviour during an infectious disease outbreak can help to protect vulnerable populations and guide equity-driven interventions. The COVID-19 pandemic probably exerted different stresses on individuals in different sociodemographic groups and ensuring fair access to and usage of COVID-19 tests was a crucial element of England's testing programme. We aimed to investigate the relationship between sociodemographic factors and COVID-19 testing behaviours in England during the COVID-19 pandemic. METHODS: We did a population-based study of COVID-19 testing behaviours with mass COVID-19 testing data for England and data from community prevalence surveillance surveys (REACT-1 and ONS-CIS) from Oct 1, 2020, to March 30, 2022. We used mass testing data for lateral flow device (LFD; data for approximately 290 million tests performed and reported) and PCR (data for approximately 107 million tests performed and returned from the laboratory) tests made available for the general public and provided by date and self-reported age and ethnicity at the lower tier local authority (LTLA) level. We also used publicly available data on mean population size estimates for individual LTLAs, and data on ethnic groups, age groups, and deprivation indices for LTLAs. We did not have access to REACT-1 or ONS-CIS prevalence data disaggregated by sex or gender. Using a mechanistic causal model to debias the PCR testing data, we obtained estimates of weekly SARS-CoV-2 prevalence by both self-reported ethnic groups and age groups for LTLAs in England. This approach to debiasing the PCR (or LFD) testing data also estimated a testing bias parameter defined as the odds of testing in infected versus not infected individuals, which would be close to zero if the likelihood of test seeking (or seeking and reporting) was the same regardless of infection status. With confirmatory PCR data, we estimated false positivity rates, sensitivity, specificity, and the rate of decline in detection probability subsequent to reporting a positive LFD for PCR tests by sociodemographic groups. We also estimated the daily incidence, allowing us to calculate the fraction of cases captured by the testing programme. FINDINGS: From March, 2021 onwards, individuals in the most deprived regions reported approximately half as many LFD tests per capita as individuals in the least deprived areas (median ratio 0·50 [IQR 0·44-0·54]). During the period October, 2020, to June, 2021, PCR testing patterns showed the opposite trend, with individuals in the most deprived areas performing almost double the number of PCR tests per capita than those in the least deprived areas (1·8 [1·7-1·9]). Infection prevalences in Asian or Asian British individuals were considerably higher than those of other ethnic groups during the alpha (B.1.1.7) and omicron (B.1.1.529) BA.1 waves. Our estimates indicate that the England Pillar 2 COVID-19 testing programme detected 26-40% of all cases (including asymptomatic cases) over the study period with no consistent differences by deprivation levels or ethnic groups. Testing biases for PCR were generally higher than those for LFDs, in line with the general policy of symptomatic and asymptomatic use of these tests. Deprivation and age were associated with testing biases on average; however, the uncertainty intervals overlapped across deprivation levels, although the age-specific patterns were more distinct. We also found that ethnic minorities and older individuals were less likely to use confirmatory PCR tests through most of the pandemic and that delays in reporting a positive LFD test were possibly longer in populations self-reporting as "Black; African; Black British or Caribbean". INTERPRETATION: Differences in testing behaviours across sociodemographic groups might be reflective of the higher costs of self-isolation to vulnerable populations, differences in test accessibility, differences in digital literacy, and differing perceptions about the utility of tests and risks posed by infection. This study shows how mass testing data can be used in conjunction with surveillance surveys to identify gaps in the uptake of public health interventions both at fine-scale levels and across sociodemographic groups. It provides a framework for monitoring local interventions and yields valuable lessons for policy makers in ensuring an equitable response to future pandemics. FUNDING: UK Health Security Agency.

GeM-LR: Discovering predictive biomarkers for small datasets in vaccine studies.

Despite significant progress in vaccine research, the level of protection provided by vaccination can vary significantly across individuals. As a result, understanding immunologic variation across individuals in response to vaccination is important for developing next-generation efficacious vaccines. Accurate outcome prediction and identification of predictive biomarkers would represent a significant step towards this goal. Moreover, in early phase vaccine clinical trials, small datasets are prevalent, raising the need and challenge of building a robust and explainable prediction model that can reveal heterogeneity in small datasets. We propose a new model named Generative Mixture of Logistic Regression (GeM-LR), which combines characteristics of both a generative and a discriminative model. In addition, we propose a set of model selection strategies to enhance the robustness and interpretability of the model. GeM-LR extends a linear classifier to a non-linear classifier without losing interpretability and empowers the notion of predictive clustering for characterizing data heterogeneity in connection with the outcome variable. We demonstrate the strengths and utility of GeM-LR by applying it to data from several studies. GeM-LR achieves better prediction results than other popular methods while providing interpretations at different levels.

Multi-site Ultrasound-guided Fine Needle Aspiration to Study Cells and Soluble Factors From Human Lymph Nodes.

Lymph nodes (LNs) are specialized secondary lymphoid tissues essential to the priming and maintenance of adaptive immune responses, including the B cell germinal center response; thus, they are central to immunity. However, the anatomically restricted and time-resolved nature of immune priming means that sampling disease-relevant human LNs requires specialized techniques. This article describes the application of ultrasound-guided fine-needle aspiration (FNA) to sample LNs, using cervical LNs of the head and neck as an exemplar. This minimally invasive technique allows collection of both immune cells and cell-free material that are relevant to both neuroimmune diseases and basic lymphatic functions. Downstream use of cellular material can include multiplexed flow cytometry, single-cell transcriptome sequencing (RNA-seq), and B cell cultures. The cell-free supernatant can be used for proteomics or other similar 'omics approaches. This unit describes collection of samples by FNA as well as processing and storage of samples for downstream assays. © 2024 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Sampling of human cervical lymph nodes by ultrasound-guided fine-needle aspiration Alternate Protocol: Sampling of human lymph nodes by ultrasound-guided fine-needle aspiration with negative pressure Basic Protocol 2: Processing and storage of human lymph node samples.

Altered IL-6 signalling and risk of tuberculosis: a multi-ancestry mendelian randomisation study.

BACKGROUND: The role of IL-6 responses in human tuberculosis risk is unknown. IL-6 signalling inhibitors, such as tocilizumab, are thought to increase the risk of progression to tuberculosis, and screening for latent Mycobacterium tuberculosis infection before using these drugs is widely recommended. We used single nucleotide polymorphisms (SNPs) in and near the IL-6 receptor gene (IL6R), including the non-synonymous variant, rs2228145, for which the C allele contributes to reduced classic (cis) IL-6 signalling activity, to test the hypothesis that altered IL-6 signalling is causally associated with the risk of developing tuberculosis. METHODS: We performed a meta-analysis of genome-wide association studies (GWAS) published in English from database inception to Jan 1, 2024. GWAS were identified from the European Bioinformatics Institute, MRC Integrative Epidemiology Unit catalogues, and MEDLINE, selecting publicly available studies for which tuberculosis was an outcome and that included the IL6R rs2228145 SNP. Using each study's population-level summary statistics, effect estimates were extracted for each additional copy of the C allele of rs2228145. We used these estimates to perform multi-ancestry, two-sample mendelian randomisation analyses to estimate the causal effect of reduced IL-6 signalling on tuberculosis. Our primary analyses used rs2228145-C as a genetic instrument, weighted on C-reactive protein (CRP) reduction as a measure of the effect on IL-6 signalling. We also took an alternative, ancestry-specific, multiple SNP approach using IL-6 receptor plasma protein as an exposure. Additionally, we compared the effects of rs2228145 in tuberculosis with those in critical COVID-19, rheumatoid arthritis, Crohn's disease, and coronary artery disease using the summary statistics extracted from GWAS. FINDINGS: 17 GWAS were included, collating data for 19 302 individuals with tuberculosis (cases) and 1 019 821 population controls across multiple ancestries. For each additional rs2228145-C allele, the odds of tuberculosis reduced (odds ratio [OR] 0·94 [95% CI 0·92-0·97]; p=6·8 × 10-6). Multi-ancestry mendelian randomisation analyses supported these findings, with decreased odds of tuberculosis associated with readouts of reduced IL-6 signalling (0·52 [0·39-0·69] for each natural log CRP decrease; p=6·8 × 10-6), with weak evidence of heterogeneity (I2=0·315; p=0·11). Ancestry-specific, multiple SNP mendelian randomisation using increase in IL-6 receptor plasma protein as an exposure revealed a similar reduced risk of tuberculosis (OR 0·94 [95% CI 0·93-0·96]; p=2·4 × 10-10). The protective effects on tuberculosis seen with rs2228145-C were similar in size and direction to those observed in critical COVID-19 (0·66 [0·50-0·86]), Crohn's disease (0·57 [0·44-0·74]), and rheumatoid arthritis (0·45 [0·36-0·58]), all of which benefit from the therapeutic effects of IL-6 antagonism. INTERPRETATION: Our findings propose a causal relationship between reduced IL-6 signalling and lower risk of tuberculosis, akin to the effect seen in other IL-6 mediated diseases. This study suggests that IL-6 antagonists do not increase the risk of tuberculosis but rather should be investigated as therapeutic adjuncts in its treatment. FUNDING: UK National Institute for Health and Care Research, Wellcome Trust, EU European Regional Development Fund, the Welsh Government, and UK Research and Innovation.

A Bivalent Adenovirus-Vectored Vaccine Induces a Robust Humoral Response, but Does Not Protect Cynomolgus Macaques Against a Lethal Challenge With Sudan Virus.

The most recent Sudan virus (SUDV) outbreak in Uganda was first detected in September 2022 and resulted in 164 laboratory-confirmed cases and 77 deaths. There are no approved vaccines against SUDV. Here, we investigated the protective efficacy of ChAdOx1-biEBOV in cynomolgus macaques using a prime or a prime-boost regimen. ChAdOx1-biEBOV is a replication-deficient simian adenovirus vector encoding SUDV and Ebola virus (EBOV) glycoproteins (GPs). Intramuscular vaccination induced SUDV and EBOV GP-specific immunoglobulin G responses and neutralizing antibodies. Upon challenge with SUDV, vaccinated animals showed signs of disease like those observed in control animals, and no differences in survival outcomes were measured among all 3 groups. Viral load in blood samples and in tissue samples obtained after necropsy were not significantly different between groups. Overall, this study highlights the importance of evaluating vaccines in multiple animal models and demonstrates the importance of understanding protective efficacy in both animal models and human hosts.

Political and Community Logics of Emergent Disease Vaccine Deployment Anthropological Insights from DRC, Uganda and Tanzania

With a growing number of emerging infectious diseases and the rapid development of vaccines during epidemics and pandemics, public health officials at the global and national level have reported concerns about vaccine hesitancy, often attributing this to a problem of misinformation and poor understanding of risk. However, social scientists have found that vaccination perceptions are complex and multi-faceted. By focusing on the historical, cultural and political influences that affect vaccine acceptance, as well as social justice questions that examine the fair distribution of vaccines, we explore the political and community logics of vaccine deployment using a case study approach. We found differing logics depending on the vaccine and the context and argue that political and community logics come to the forefront during outbreaks as vaccine strategies often are imposed—in different ways—by the Global North. We suggest that, prior to the development and deployment of new vaccines for emergent diseases in the Global South, political level and community logics must be acknowledged and engaged with.

Serum and mucosal antibody-mediated protection and identification of asymptomatic respiratory syncytial virus infection in community-dwelling older adults in Europe.

INTRODUCTION: Respiratory syncytial virus (RSV) causes acute respiratory tract infection (ARTI) and reinfects adults throughout life, posing a risk for hospitalization in older adults (>60 years) with frailty and comorbidities. METHODS: To investigate serum and mucosal antibodies for protection against RSV infections, baseline serum samples were compared for RSV-pre- and -post-fusion (F) binding, and RSV-A2 neutralizing IgG antibodies between symptomatic RSV-ARTI (N = 30), non-RSV (RSV negative) ARTI (N = 386), and no ARTI (N = 338). Mucosal RSV-pre-F IgA and IgG levels, as well as serum RSV-G IgG antibodies, were analyzed to determine their association with protection from symptomatic RSV-ARTI in a subset study. RESULTS: Using a receiver operating characteristic (ROC) analysis, we established thresholds of 1.4- to 1.6-fold change (FC) for RSV-pre-F and -post-F, and RSV-A2 neutralizing IgG antibodies, respectively, enabling the identification of asymptomatic RSV cases with high sensitivity and specificity (>80% and >90%, respectively). As a result, serum RSV-pre-F, RSV-G IgG, and mucosal pre-F binding IgA antibodies showed correlations with protection against symptomatic RSV infection. RSV-pre-F IgG antibodies were correlated with protection from RSV infections irrespective of the symptoms. DISCUSSION: This study provides insights into antibody-mediated protection for symptomatic RSV infection in a community-dwelling older-adult population and establishes a threshold to identify asymptomatic RSV infection using a data-driven approach.

Development and characterization of high-throughput serological assays to measure magnitude and functional immune response against S. Paratyphi A in human samples

Typhoid and Paratyphoid fever cause a global health burden, especially for the children of Southern Asia. The impact of the disease is further exacerbated by the dramatic increase of antimicrobial resistance. While vaccines against Salmonella Typhi have been developed and successfully introduced, an effective vaccine targeting S. Paratyphi A is still lacking. Several efforts are currently ongoing to develop vaccines targeting both S. Typhi and S. Paratyphi A. In order to analyze the immune response induced by vaccination and in sero-epidemiological studies, easy to perform and high throughput immunoassays are needed. Here we present the setup and characterization of a customized ELISA assay and of a luminescent-based serum bactericidal assay (L-SBA) to measure the quantity of S. Paratyphi O antigen specific antibodies and their functional activity against S. Paratyphi A. Robust quality control criteria have been put in place both for ELISA and SBA and assays have been fully characterized in terms of quantitation limit, limit of blanks, specificity, linearity and precision. Assays are being employed to analyze samples from clinical trials, enabling the assessment of immunogenicity during clinical vaccine development.

Essential role of proline synthesis and the one-carbon metabolism pathways for systemic virulence of Streptococcus pneumoniae.

Virulence screens have indicated potential roles during Streptococcus pneumoniae infection for the one-carbon metabolism pathway component Fhs and proline synthesis mediated by ProABC. To define how these metabolic pathways affect S. pneumoniae virulence, we have investigated the phenotypes, transcription, and metabolic profiles of Δfhs and ΔproABC mutants. S. pneumoniae capsular serotype 6B BHN418 Δfhs and ΔproABC mutant strains had strongly reduced virulence in mouse sepsis and pneumonia models but could colonize the nasopharynx. Both mutant strains grew normally in complete media but had markedly impaired growth in chemically defined medium, human serum, and human cerebrospinal fluid. The BHN418 ΔproABC strain also had impaired growth under conditions of osmotic and oxidative stress. The virulence role of proABC was strain specific, as the D39 ΔproABC strain could still cause septicemia and grow in serum. Compared to culture in broth, in serum, the BHN418 Δfhs and ΔproABC strains showed considerable derangement in global gene transcription that affected multiple but different metabolic pathways for each mutant strain. Metabolic data suggested that Δfhs had an impaired stringent response, and when cultured in sera, BHN418 Δfhs and ΔproABC were under increased oxidative stress and had altered lipid profiles. Loss of proABC also affected carbohydrate metabolism and the accumulation of peptidoglycan synthesis precursors in the BHN418 but not the D39 background, linking this phenotype to the conditional virulence phenotype. These data identify the S. pneumoniae metabolic functions affected by S. pneumoniae one-carbon metabolism and proline biosynthesis, and the role of these genetic loci for establishing systemic infection.IMPORTANCERapid adaptation to grow within the physiological conditions found in the host environment is an essential but poorly understood virulence requirement for systemic pathogens such as Streptococcus pneumoniae. We have now demonstrated an essential role for the one-carbon metabolism pathway and a conditional role depending on strain background for proline biosynthesis for S. pneumoniae growth in serum or cerebrospinal fluid, and therefore for systemic virulence. RNAseq and metabolomic data demonstrated that the loss of one-carbon metabolism or proline biosynthesis has profound but differing effects on S. pneumoniae metabolism in human serum, identifying the metabolic processes dependent on each pathway during systemic infection. These data provide a more detailed understanding of the adaptations required by systemic bacterial pathogens in order to cause infection and demonstrate that the requirement for some of these adaptations varies between strains from the same species and could therefore underpin strain variations in virulence potential.

Navigating vaccine procurement and financing challenges in Cameroon: Insights and recommendations from a mixed-methods study (2015-2020).

OBJECTIVES: Vaccine stockouts at the national level has been recognized as a critical challenge in ensuring sustained and equitable immunization coverage. These stockouts often arise from inherent issues within countries, including delays in government funding, suboptimal forecasting and stock management practices, and inefficiencies in the procurement process amongst others. Understanding the complexities and barriers within vaccine procurement and financing systems is crucial for developing effective strategies to enhance vaccine availability and strengthen immunization programs. This is particularly relevant in the context of reaching zero dose children and transitioning from Gavi. This study aimed to comprehensively assess the vaccine procurement and financing landscape in Cameroon from 2015 to 2020. STUDY DESIGN: This was a descriptive cross-sectional study. METHODS: Employing a mixed-methods approach, we conducted a desk review of pertinent documents and engaged in in-depth interviews with key stakeholders involved in the procurement and funding mobilization processes. Through data collection and analysis using Microsoft Excel 365 and Dedoose software, we delineated the intricacies of the procurement process and pinpointed specific barriers that have contributed to vaccine stockouts. RESULTS: The mapping of vaccine procurement processes revealed complexity, protracted timelines, and the involvement of multiple stakeholders. The Expanded Program on Immunization (EPI) faced a USD 4 million funding deficit for vaccine procurement between 2016 and 2019. Consequently, the program experienced delays in acquiring 20 million vaccine doses, leading to 41 months of stockout for at least one antigen. Major bottlenecks identified by key stakeholders in vaccine procurement and financing encompassed delayed fund mobilization, inefficient and lengthy processes for fund mobilization and disbursement, poor data utilization, and discrepancies between forecasted, allocated, and mobilized funds. CONCLUSION: The findings of this research hold significant implications for many EPIs. By elucidating procurement and financing challenges, we can formulate evidence-based recommendations aimed at optimizing resource allocation, streamlining procurement processes, and bolstering vaccine availability. These insights are essential for fostering collaboration between government agencies, technical partners, and financial partners to achieve sustainable vaccine access in Cameroon. Establishing a joint procurement working group could streamline processes, potentially reducing stockouts and improving vaccine coverage.

5-year vaccine protection following a single dose of Vi-tetanus toxoid conjugate vaccine in Bangladeshi children (TyVOID): a cluster randomised trial.

BACKGROUND: WHO currently recommends a single dose of typhoid conjugate vaccine (TCV) in high-burden countries based on 2-year vaccine efficacy data from large randomised controlled trials. Given the decay of immunogenicity, the protection beyond 2 years is unknown. We therefore extended the follow-up of the TyVAC trial in Bangladesh to assess waning of vaccine protection to 5 years after vaccination. METHODS: We conducted a cluster randomised controlled trial (TyVAC; ISRCTN11643110) in Dhaka, Bangladesh, between 2018 and 2021. Children aged 9 months to 15 years were invited to receive a single dose of TCV or Japanese encephalitis vaccine between April 15, 2018, and November 16, 2019, based on the randomisation of their clusters of residence. Children who received the Japanese encephalitis vaccine were invited to receive TCV at the final visit between Jan 6, and Aug 31, 2021, according to the protocol. This follow-on study extended the follow-up of the original trial until Aug 14, 2023. The primary endpoint of this study was to compare the incidence of blood culture-confirmed typhoid between children who received TCV in 2018-19 (the previous-TCV group) and those who received the vaccine in 2021 (the recent-TCV group), to evaluate the relative decline in vaccine protection. We also did a nested study using the test-negative design comparing the recent-TCV and previous-TCV groups with unvaccinated individuals, as well as an immunogenicity study in a subset of 1500 children. FINDINGS: Compared with the recent-TCV group, the previous-TCV group had an increased risk of typhoid fever between 2021-23, with an adjusted incidence rate ratio of 3·10 (95% CI 1·53 to 6·29; p<0·0001), indicating a decline in the protection of a single-dose of TCV 3-5 years after vaccination. The extrapolated vaccine effectiveness in years 3-5 was 50% (95% CI -13 to 78), and was validated using the test-negative design analysis, with a vaccine effectiveness of 84% (74 to 90) in the recent-TCV group and 55% (36 to 68) in the previous-TCV group, compared with unvaccinated individuals. Anti-Vi-IgG responses declined over the study period. The highest rate of decay was seen in children vaccinated at younger than 2 years in the original trial. The inverse correlation between age and the decay of antibodies was also seen in the subgroup analysis of vaccine effectiveness, where the youngest age group (<7 years at fever visits) exhibited the fastest waning, with vaccine effectiveness dropping to 24% (95% CI -29 to 55) at 3-5 years after vaccination. INTERPRETATION: A decline in the protection conferred by a single-dose TCV was observed 3-5 years after vaccination, with the greatest decline in protection and immune responses observed in children vaccinated at younger ages. A booster dose of TCV around school entry age might be needed for children vaccinated while younger than 2 years to sustain protection against typhoid fever during the school years when the risk is the highest. FUNDING: The Bill & Melinda Gates Foundation.

Distinct glycosylation and functional profile of typhoid vaccine-induced antibodies in a UK challenge study and Nepalese children.

A blood atlas of COVID-19 defines hallmarks of disease severity and specificity.

Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete description of specific immune biomarkers. We present here a comprehensive multi-omic blood atlas for patients with varying COVID-19 severity in an integrated comparison with influenza and sepsis patients versus healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity involved cells, their inflammatory mediators and networks, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism, and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Systems-based integrative analyses including tensor and matrix decomposition of all modalities revealed feature groupings linked with severity and specificity compared to influenza and sepsis. Our approach and blood atlas will support future drug development, clinical trial design, and personalized medicine approaches for COVID-19.

MCMV-based vaccine vectors expressing full-length viral proteins provide long-term humoral immune protection upon a single-shot vaccination.

Global pandemics caused by influenza or coronaviruses cause severe disruptions to public health and lead to high morbidity and mortality. There remains a medical need for vaccines against these pathogens. CMV (cytomegalovirus) is a β-herpesvirus that induces uniquely robust immune responses in which remarkably large populations of antigen-specific CD8+ T cells are maintained for a lifetime. Hence, CMV has been proposed and investigated as a novel vaccine vector for expressing antigenic peptides or proteins to elicit protective cellular immune responses against numerous pathogens. We generated two recombinant murine CMV (MCMV) vaccine vectors expressing hemagglutinin (HA) of influenza A virus (MCMVHA) or the spike protein of severe acute respiratory syndrome coronavirus 2 (MCMVS). A single injection of MCMVs expressing either viral protein induced potent neutralizing antibody responses, which strengthened over time. Importantly, MCMVHA-vaccinated mice were protected from illness following challenge with the influenza virus, and we excluded that this protection was due to the effects of memory T cells. Conclusively, we show here that MCMV vectors induce not only long-term cellular immunity but also humoral responses that provide long-term immune protection against clinically relevant respiratory pathogens.

Obesity differs from diabetes mellitus in antibody and T-cell responses post-COVID-19 recovery.

OBJECTIVE: Obesity and type 2 diabetes (DM) are risk factors for severe coronavirus disease 2019 (COVID-19) outcomes, which disproportionately affect South Asian populations. This study aims to investigate the humoral and cellular immune responses to SARS-CoV-2 in adult COVID-19 survivors with overweight/obesity (Ov/Ob, BMI ≥ 23 kg/m2) and DM in Bangladesh. METHODS: In this cross-sectional study, SARS-CoV-2-specific antibody and T-cell responses were investigated in 63 healthy and 75 PCR-confirmed COVID-19 recovered individuals in Bangladesh, during the pre-vaccination first wave of the COVID-19 pandemic in 2020. RESULTS: In COVID-19 survivors, SARS-CoV-2 infection induced robust antibody and T-cell responses, which correlated with disease severity. After adjusting for age, sex, DM status, disease severity, and time since onset of symptoms, Ov/Ob was associated with decreased neutralizing antibody titers, and increased SARS-CoV-2 spike-specific IFN-γ response along with increased proliferation and IL-2 production by CD8 + T cells. In contrast, DM was not associated with SARS-CoV-2-specific antibody and T-cell responses after adjustment for obesity and other confounders. CONCLUSION: Ov/Ob is associated with lower neutralizing antibody levels and higher T-cell responses to SARS-CoV-2 post-COVID-19 recovery, while antibody or T-cell responses remain unaltered in DM.

Respiratory Syncytial Virus-related Community Chronic Obstructive Pulmonary Disease Exacerbations and Novel Diagnostics: A Binational Prospective Cohort Study.

Rationale: Respiratory syncytial virus (RSV) is a common global respiratory virus that is increasingly recognized as a major pathogen in frail older adults and as a cause of chronic obstructive pulmonary disease (COPD) exacerbations. There is no single test for RSV in adults that has acceptable diagnostic accuracy. Trials of RSV vaccines have recently shown excellent safety and efficacy against RSV in older adults; defining the frequency of RSV-related community infections and COPD exacerbations is important for vaccine deployment decisions. Objectives: This prospective study aimed to establish the frequency of outpatient-managed RSV-related exacerbations of COPD in two well-characterized patient cohorts using a combination of diagnostic methods. Methods: Participants were recruited at specialist clinics in London, United Kingdom, and Groningen, the Netherlands, beginning in 2017 and observed for three consecutive RSV seasons, during exacerbations, and at least twice yearly. RSV infections were detected by RT-PCR and serologic testing. Measurements and Main Results: A total of 377 patients with COPD attended 1,999 clinic visits and reported 310 exacerbations. There were 27 RSV-related exacerbations (8.7% of the total); of these, seven were detected only by PCR, 16 only by serology, and four by both methods. Increases in RSV-specific Nucleoprotein antibody were as sensitive as those in the antibody to Pre-Fusion or Post-Fusion for serodiagnosis of RSV-related exacerbations. Conclusions: RSV is associated with 8.7% of outpatient-managed COPD exacerbations in this study. Antibodies to RSV Nucleoprotein may have diagnostic value and are potentially important in a vaccinated population. The introduction of vaccines that prevent RSV is expected to benefit patients with COPD.